Infectious Diseases

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Rickettsiae are obligate intracellular gram-negative bacteria that are associated with arthropod vectors. Currently, the Rickettsia genus contains 25 officially validated species, of which 16 are human pathogens and 2 are suspected to cause Rickettsioses. The members of the Rickettsia genus are divided into 2 groups according to their pathogenicity and their phenotypic properties:

The spotted fever group (SFG)

Typhus group (TG)

R. bellii and R. canadensis belong to different groups

5 Rickettsial genes (16S rDNA, gltA, ompA, ompB, and sca4 genes) are proposed to determine new genus and species of Rickettsiae

These zoonoses are among the oldest known vector-borne diseases, but new species continue to be describing in vectors and in human samples. Among them, some have a role in human pathology.

Rickettsia is mainly associated with ticks, but also lice, fleas and mites, and causes spotted fevers or typhus in humans

Rickettsiae are strictly intracellular bacteria whose size range from 0.3 x 0.8 µm to 0.5 x 2 µm, and have cell wall and lipopolysaccharide similar to other gram negative bacteria.

Not visible by gram staining but is visible by Gimenez or Giemsa staining

These bacteria live free in the cytoplasm and divide by binary fission in the cytoplasm

Traditional methods used in bacteriology cannot be routinely applied to Rickettsiae because of their intracellularity

Several host factors such as age (>60 years), comorbidities (chronic alcoholism, diabetes), immunosuppression, and deficiency in G6PD are associated with more severe disease and more fatalities.

What are the clinical manifestations of infection with this organism?

Typically, the clinical symptoms of spotted fever Rickettsioses include fever, headache, myalgia, cutaneous rash, local lymphadenopathy and a characteristic inoculation eschar. But these clinical signs, and the severity and outcome of the disease, vary depending on the Rickettsial specie involved.

Tick-borne Rickettsioses

Mediterranean Spotted fever (MSF)

The causative agent is Rickettsia conorii subsp. conorii. Recently it has been proposed to modify the nomenclature of the R. conorii species through the creation of 4 subspecies (R. conorii subsp. conorii, R. conorii subsp. israelensis, R. conorii subsp. caspia, R. conorii subsp. indica) to accommodate both the genotypic homogeneity, geographic and pathogenic diversities of Rickettsia strains within this species.

The main vector is the worldwide dog tick, Rhipicephalus sanguineus.

MSF have seasonal distribution, it is a summer illness with most cases occurring between July and September. Recent study supports that warmer weather is linked to an increase in the aggressiveness of R. sanguineus.

MSF is endemic in the Mediterranean area, including Northern Africa and Southern Europe, and is also found in Central Europe and Central Africa.

The incubation period lasts around 6 days (1-16 days) and is asymptomatic.

MSF in the endemic zone is characterized by the association of:

fever, onset is abrupt with high (>39°C)

flu-like symptoms

maculopapular rash occurs 2 to 3 days after the fever, it is initially macular then maculopapular and generalized; palm and face is generally spared.

Black eschar at the bite site:

Indolent and usually present on the trunk and the limbs and are rarely multiple.

The duration of illness is between 12 to 20 days

Clinical improvement occurs within 48 hours of antibiotic treatment.

Severe forms include:

major neurological manifestations

multi-organ involvement which may occur in 5% of patients.

Recent MSF appears to be a more severe disease than it was in the past. The mortality rate is usually estimated at around 1%, but increased to 32.3% in Portugal in 1997.

Israeli spotted fever (ISF)

Rickettsia conorii subsp. israelensis

Also transmitted by R. sanguineus

Found in Israel

Also associated with human disease in Portugal and Sicily, suggesting that the geographical distribution is wider than previously thought.

Several recent studies show the efficacy and the reliability of swabs of eschars or vesicular lesions for molecular diagnosis of Rickettsioses.

Real-time PCR more recently developed is often used with primer and probes targeting various Rickettsial genes which can be used with suitable facilities in any laboratory.

Rickettsia can be detected directly in tissue specimen, particularly skin biopsy by histochemical stains as Giemsa or Gimenez, as well as immunohistochemical methods.

How does this organism cause disease?

Humans are infected by SFG Rickettsia directly by inoculation into the blood by an infected arthropod. In blood vessels, the bacteria penetrate in vascular endothelial cells by interaction between a host cell receptor (Ku70) and an adhesive (OmpB), an abundant surface protein of Rickettsia. This interaction triggered an enzymatic cascade inducing alteration of cytoskeletal actin at the entry site to phagocytose the Rickettsia. The bacterium is internalized in a phagosome and the Rickettsia lysed the cell membrane of the phagosome by secretion of phospholipase D and haemolysin C, and escape into the cytosol where they are divided by binary fission. The bacteria move into the cytosol by actin polymerization. The protein RickA stimulates activation of Arp2/3 which mediates polymerization of host actin at one of the poles of the bacterium and allow the Rickettsia to spread into the adjacent cells. The ability of the SFG Rickettsia to spread from cell to cell without passing through the intracellular space enable bacteria to evade the immune response and thus, contribute to the development of the infection to penetrate into others cells and sometimes enter the cell nucleus.

Most of the clinical characteristics of SFG Rickettsia are attributed to disseminated infection of the endothelium, where the bacteria grow and stimulate oxidative stress causing death of endothelial cells. The effect of Rickettsia in endothelial cells include an increase in microvascular permeability due to the disruption of junctions between infected endothelial cells, a generalized vascular inflammation, oedema, increased interaction between leukocytes-endothelium, and release of vasoactive mediator that promote coagulation and pro-inflammatory cytokines.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?